Monoesters of phosphonic acids



United States Patent Oil 3,350,481 MONOESTERS F PHOSPHONIC ACIDS Emile Cherbuliez and Joseph Rabinowitz, Geneva, Switzerland, amignors to Hooker Chemical Corporation, Niagara Falls, N.Y., a corporation of New York No Drawing. Filed Nov. 24, 1965, Ser. No. 509,645 3 Claims. (Cl. 260-961) This is a continuation-in-part of 'United States patent application Ser. No. 230,315, filed Oct. 11, 1962, now US. Patent No. 3,268,629.

The present invention relates to new phosphonic monoesters and to an improved on corresponding dichlorides.

It is sufiicient to (R-PO with 0.5 to 3 moles, especially with 1.2 to 3 Generally, the phosphonic monoester is separated from the mixture in the form of its salt which may be characterized by the formula In the above formulas, R has the significance indicated previously, R represents aliphatic radicals such as alkyl, alkenyl, alkynyl, cycloalkyl, cycloalkenyl, cycloalkynyl, or

3,350,481 Patented Oct. 31, 1967 ice bicycloalkyl, araliphatic radicals such as aralkyl, aromatir radicals such atoms, particultarly chlorine or fluorine, free or esterified hydroxyl or carboxyl groups, carboxamide, nitrile or amino preferably tertiary-substituted amino for example, aliphatic radicals stituents may be found in any indicated radicals with respect phonated.

Thus, this reaction is a general one and applies to various alcoho percentage of phosphomc amide. This amidlzed group may, if desired, be readily hydrolyzed in an acid medium when the ester portion is relatively stable.

phonation of a secondary alcohol.

A preferred embodiment of this invention is the reaction of an alcohol with carboxamido alcohol. With 13-, 7 and 5-nitrilo alcohols the monoesters of the nitrilo alcohols are tained; the hydrolysis to the carboxamido not take place.

The monoesters obtained can be isolated as their metal salts. The alkaline or alkaline earth metal salts of phosphonic monoesters are practically phonic monoesters of amino alcohols are alkaline in aqueous solution (pH 105-11) and also are stable at this pH.

In order to isolate the alkaline earth metal or alkali metal salts of the phosphonic monoester, including the calcium, barium, strontium, sodium, potassium, lithium, aluminum and magnesium salts, one proceeds as follows.

After cooling, the excess alcohol is distilled (when a large excess is used) under vacuum. The residue is taken up by water and neutralized by a hydroxide of an alkaline earth metal to a pH of 8.2 (turning of phenolphthalein). (In the case of amino alcohols, it is desirable to add hydroxide sufficient to obtain a pH of about 11.) The phosphonic acid which may still be present (formed by hydrolysis of the oxide which may not have reacted, or formed in the course of the reaction when polyphosphonic acid is used) precipitates partially as an alkaline earth metal salt; it is completely precipitated by the addition of one volume of alcohol. This is filtered and the filtrate which contains the alkaline earth metal salt of the phosphonic monoester is evaporated and dried under vacuum. Generally, the product obtained is pure. If not, it is purified by extraction with boiling acetone (which dissolves the impurities); after cooling, the alkaline earth metal salt of the phosphonic monoester is filtered.

If it is desired to obtain alkali metal salts of these monoesters, the alkaline earth metal salt is dissolved in water and there is added the required quantity of carbonate of an alkali metal. The precipitate of the alkaline earth metal carbonate formed is filtered ofi and the filtrate is evaporated to dryness under vacuum. The amorphous residue treated by acetone is transformed into a crystalline precipitate which is the alkali metal salt of the monoester. One may adapt the above methods to make other salts.

The alkaline earth metal salts of the phosphonic monoesters of superior aliphatic alcohols or of terpene alcohols are generally insoluble in water or in 50 percent ethyl alcohol. In order to isolate these monoesters, one proceeds preferably as follows:

(a) After cooling, the reaction mass is taken up by ether and neutralized by triethylamine. The triethylammonium salt of the phosphonic acid is filtered ofi, whereas the triethylammonium salt of the phosphonic monoester is soluble. The ether and the excess of the tertiary base are distilled, the residue is taken up by ether and the alkali earth metal salt of the phosphonic monoester is precipitated by adding an aqueous solution of the corresponding alkali earth metal halogenide. The precipitate is washed with water and is purified as previously described.

(b) If the reaction is carried out in the presence of a tertiary base such as trimethylamine, triethylamine or pyridine, the reaction mixture is taken up by ether and the phosphonate of the tertiary amine is filtered off. The ether and the excess of the tertiary base are distilled and the residue is taken up by water. The alkaline earth metal salt of the phosphonic monoester is precipitated by adding an aqueous solution of an alkali earth metal halogenide.

If the free phosphonic monoester crystallizes easily, the reaction mixture is taken up by water and the free phosphonic monoester is precipitated by adding a strong acid, such as hydrochloric acid (this is the case, for instance, of menthyl phenylphosphonic acid).

This new process of phosphonation of alcohols by phosphonic oxides and polyphosphonic acids has a number of advantages: it leads straight to monoesters only, it is simple and directly gives pure products in very high yield, calculated as a percentage of the theoretical value. Moreover, the process is quite general and many of the prepared phosphonic monoesters are new.

The monoesters thus obtained and their salts may be used as pharmaceutical products or as intermediates for the production of such and other products, as additives to liquid fuels, such as pregnating fibers so as sistant or vermin-proof.

The invention is illustrated but not limited by the following examples. All parts are by weight and all temperatures are in degrees centigrade, unless otherwise indicated.

Example 1 140 parts (1 equivalent) of phenylphosphonic oxide (C H -PO and 48 to 64 parts (1.5 to 2 moles) of anhydrous methanol are heated to 100 degrees centigrade (bath temperature). After cooling, the excess alcohol is evaporated under vacuum and the residue is taken up with 500 to 800 parts of H 0. This solution is neutralized by Ca(OH) (or Ba(OI-I) if one desires to obtain a barium salt of the monoester) up to a pH at which phenolphthalein turns to colored form (about 8.2). Then an equal volume of alcohol is added and the calcium (or barium) phenylphosphonate thus precipitated is filtered. The filtrate, evaporated to dryness, yields the monomethylphenylphosphonate of calcium (or barium) which is generally pure initially. If it is not, the dry residue is dissolved in boiling acetone and, after cooling, the calcium or barium monomethylphenylphosphonate is filtered. The yield in pure product,

O CH:

Example 2 The phenylphosphonic monoesters (in the form of their calcium or barium salts) of the alcohols mentioned below have been prepared in the same manner as described in Example 1.

The monoester of ethanol of the formula:

II C6H5P-O 02H] Yield='84 percent.

The monoester of propanol of the formula:

lt/ CoHs-P-O CHzCHzCH;

Yield=90 percent.

The monoester of isopropanol of the formula:

(IT/0M OuHr-P-O CH(CH:):

Yield=56 percent.

The monoester of butanol of the formula:

fi/OM CsH5-POCH2CH1CH1GH8 Yield= percent.

The monoester of isobutanol of the formula:

f/0M CaHs-PO CH(CHz)-CH2CH:

Yield=60 percent.

The monoester of amyl alcohol of the formula:

(fi/OM C5H5PO CHzCHzCHzCHzCH; Yield=7l percent.

In all the above formulas M is Ca or B21 Example 3 The esters described in Examples 1 and 2 were also obtained with the aid of polyphenylphosphonic acid (n-Z) as the phosphonating agent, in the following manner:

In a flask connected in an oil bath,

Example 4 140 parts (1 equivalent) of phenylphosphonic oxide and 84 to 112 parts (1.5 to 2.0 moles) of propargyl alto 90 degrees centigrade. One then isoand the yield is 70 percent.

By infrared spectroscopic examinatiomthe presence of the -C=-C group is verified.

In the same manner, there is prepared in 90 percent yield, phenylphosphonic monoester of allyl alcohol All of these are new products. In the above formulas M=Ca or Ba Example 5 140 parts and 120 to 161 are heated for 16 temperature). After cooling, the excess of chlorohydrin is distilled oif under vacuum and one isolates the barium salt of the mono (Z-chlordethyl)phenylphosphonic acid,

in a yield of 85 percent.

In a similar manner, except for the temperature and duration of heating (which are shown in parentheses), the phosphonic monoesters of halogenated alcohols mentioned below are obtained, with yields indicated.

Phenylphosphonic monoester (100 degrees of 3-chloropropanol-l centigrade, 16 hours) of the formula:

OH C H l O O CHzCHzCHzCI Yield=84 percent.

Phenylphosphonic monoester of 4-chlorobutanol-1 (50 degrees centigrade, 16 hours) of-the formula:

OM C ll -P40 OCHzCHzCHzCHgCl Yield= percent.

Phenylphosphonic monoester of 1,3-difluoropropanol-2 (130 degrees Centigrade, 48 hours) of the formula:

(III) OM CaH5P o CH(C 02F Yeld=56 percent.

Phenylphosphonic monoester of 3-fluor0propanol-1 (100 degrees Centigrade, 48 hours) of the formula:

Example 6 140 parts (C H PO and 91 to 124 parts (1.5 to 2.0 moles) of in the manner described in Example 1, with a yield of 60 percent.

v Yield=65 percent.

The' phenylphosphonic monoester (here the reaction takes place for 48 hours) of the formula:

CaH5-PO CH2 CH2 CHzCHzOH Yield: 72 percent.

of butanediol-l,4 at 50 degrees centigrade,

Phenylphosphonic monoester of pentanediol-1,5 of the formula:

0 0M C -1i0CHzCHzCHzCHgCHaOH Yield=77 percent.

In the case of butanediol-l,4-(tetramethyleneglycol), the temperature should not exceed 60 degrees centigrade, in order to avoid the formation of tetrahydrofurane in the phosphonation process.

Also, even if there is used a large excess of a phosphonating agent, only one group -OH is phosphonated.

All of these esters are new.

In the formulas given M=Ca or B395.

Example 7 140 parts (1 equivalent) of phenylphosphonic oxide and 267 to 336 parts (3 to 4 moles) of dimethylcolamine (dimethylaminoethanol) are heated for'3 hours at 120 degrees centigrade. The excess of dimethylcolamine is distilled off under vacuum and the residue is dissolved in 800 to 1000 parts of water. There is then added an excess of calcium hydroxide in suspension in water with the mixture being agitated for several minutes. After filtering, one volume of alcohol is added to the filtrate to completely precipitate the calcium phenylphosphonate still present. This is followed by further filtration and evaporation under vacuum. An amorphous residue is obtained, which, after being treated with boiling acetone, cooled and filtered, yields a precipitate of calcium dimethylaminoethylphenylphosphonate. The formula of this compound CgHr-P O CH2CH2N (CH3) 2 and it was obtained in 50 percent yield.

In treating 1-diethylaminopropanol-2 in the above described manner, there is obtained by evaporation under vacuum an aqueous alcoholic solution of calcium (l-diethylaminopropyl-2 phenylphosphonate,

C5H5-P OCH-CH3 H2N(C2 a)2 which is pure. The yield is 30 percent.

Example 8 140 parts (1 equivalent) of phenylphosphonic oxide and 152.5 (2.5 moles) of colamine are heated at 180 degrees centigrade (bath temperature) up to the point where the mass becomes homogenous. Then a vacuum is created in the flask, which is kept at this temperature overnight. After cooling, the reactive mass is dissolved in 800 to 1000 parts of water with the addition of an excess of calcium hydroxide. This mixture is agitated and an equal volume of ethanol is added. The liquid is filtered and evaporated dry under vacuum. The residue is treated with boiling alcohol and yields, after cooling, a precipitate of calcium (Z-aminoethyl)phenylphosphonate,

(H /0 Cam uHs-P O CHzCHaNH-z in 40 percent yield.

Example 9 (R/Olll eHs-f-O C HM is obtained in a yield of 60 percent by isolation in the manner described under Example 1.

Example 10 One mole of cetylic alcohol and one equivalent of phenylphosphonic oxide are heated for 48 hours at 110 degrees centigrade. After cooling, the reaction mixture is taken up by ether and four equivalents of triethylamine are added. The precipitate of triethylammonium phenylphosphonate is filtered off, whereas the triethyl-ammonium salt of the monoester is soluble. The ether and excess of triethylamine are evaporated under reduced pressure and the residue is taken up by ether. This solution, treated with aqueous barium chloride, yields a gelatinous precipitate which is filtered off, washed with water and then with acetone and ether, and finally dried in vacuum over P 0 The yield is 50 percent of pure barium cetyl phenylphosphonate:

CH (CH CH OH or CHF (CF CH OH, and when using the described procedure, the following barium phenylphosphonic monoesters are obtained:

(fi/OBtlos oH5P-0 CHAOHMOH;

Yield= percent.

ll CaH5-P-O OH2(CHI) 30H;

Yield=23 percent.

ll c r-I,1 0 oiiitormoilri Yield=55 percent.

Example 11 One mole of nerol, two moles of triethylamine and one equivalent of phenylphosphonic oxide are mixed carefully (the reaction is exothermic and it is necessary to cool). After a few minutes the mixture becomes homogeneous. It is then heated at 100 degrees centigrade for 15 hours (with good agitation). After cooling, the reaction mass is taken up by anhydrous ether. The triethylammonium phenylphosphonate is filtered off and the ether and the excess of triethylamine are evaporated under reduced pressure. The oily residue is dissolved in water and the pH brought to about 5, by adding dilute hydrochloric acid. When an excess of a concentrated aqueous solution of calcium chloride is added to the preceding solution, voluminous precipitate of the calcium salt of the phenylphosphonic monoester appears. This precipitate, which retains most of the unreacted terpene alcohol, is washed with water and then with acetone which dissolves most of the retained alcohol. To achieve the elimination of the retained alcohol, the precipitate is finally washed with ether and then dried in vacuo over P 0 The yield is 30 percent of pure calcium neryl phenylphosphonate C H O PCa In a similar manner, the calcium salts of the phenylphosphonie monoesters of geraniol and farnesol are ob tained in 31 percent yield each.

Example 12 Three moles of menthol, 3 moles of pyridine and 3 equivalents of phenylphosphonic oxide are mixed very carefully until the mass liquefies and becomes homogenous. The mixture is then heated for 15 hours at 70-75 degrees centigrade. After cooling, the reaction mixture is taken up by water. This solution is introduced slowly and with agitation in normal hydrochloric acid (3 liters). The precipitate of menthylphenylphosphonic acid is filtered off, washed with water and then heated at degrees centigrade, in vacuo, for one night, in order to eliminate any trace of menthol which has been retained by the precipitate. In this manner, pure menthyl phenylphosphonic acid,

3,350,481 9 1'0 C H O P, melting point 91 degrees centigrade, is obwater to five liters. One volume of alcohol is added an tained in an 81 percent yiel the barium phenylphosphonate is filtered 015?. The filtrat In a similar manner, bornyl phenylphosphonic acid, is evaporated to dryness under vacuum, and the residu C H O P, melting point 104-105 degrees centigrade, is treated with ether (in order to dissolve any traces of re prepared from borneol in an 88 percent yield. 5 tained tribromoethanol) yields the pure barium tribro Example 13 Irilrlclaleztl ryl phenylphosphonate having the following for One mole of lactonitrile and one equivalent of phenyl- CBr -CH OP(O) (C H (OBa phosphomc oxide are heated at 90 degrees centigrade for Yield: 70 percent.

In a similar manner are prepared the phenylphosphonic cold water and is quickly neutralized by barium hydroxlde to a pH of 8 2 (turning of phenolphthalem) One volume g gfii gzi gg g tnchlomlsopropanol and of the barium phenylphosphonate which is filtered off and CCI CH OP(O) (C H (OBa 5 Yield: 88 percent.

is treated again several times with acetone in order to a e o.5) 3 eliminate completely any trace of lactonitrile that would Yield; 73 Percent barium 2-carbamido-2-ethyl phenylphosphonate is 89 per- CFFCHZOHO) (C6H5) (03am) cent. Yield: 81 percent.

The a-nitrilo alcohols are transformed, under the de- Example 16 Scnbed commons the correspondmg carboxanlnqo' In a similar manner as described in Examples 1 to 15, alkyl phenylphosphomc monoesters, 13-, 'yand 6-n1tr1lo 1 h 1 1d the di 1k 1 h n 1 hos p-fluorophenylphosphomc monoesters are ootarned in good a co s yle correspon ng m n 0a y p e y p yields when p-fiuorophenylphosphonic oxide (a novel oxphonic monoesters.

In a similar manner are phosphonated the nitrilo alcohols of the following formulas (yield of the barium salt of Using for examp as Stamng alcohols: methanol tbutanol, t-amyl alcohol, propane-1,3-diol, 2-chloro-1-ethanol, n-decanol, 2-amino-l-ethanol, Z-dimethylarnino-lcent);NC-C(CH OH (64 percent); NC-CH CH OH P N C CH 3 2 OH p ethanol, lactomtnle and 2amtrilo 1 ethanol, the following 2 2 2 p p-fluorophenylphosphonic monoesters are obtained:

RP(O)(OM)(OCH) (70%) N O s C (CH2)? H (CH COP(O)(R)(OM) 53% (59 percent). The first two nitrilo alcohols yield the cor- 35 3 1.1 )(CH3 cop o (R) (OM) (16% responding carboxamidoalkyl phenylphosphonic mono- HOCHZCHZCHZOHOMR) (0M) (79% esters and the other nitrilo alcohols (13-, 'yand 6-nitrilo ClCH CH OP(O)(R) (OM) (62%) alcohols) yield the corresponding nitriloalkyl phenylphos- CH (CH CH OP( (R) (GM) 2% phonic monoesters. H NCH CH OP(O)(R) (OM) (53%) l 40 (CH NCH CH OP(O) (R) (OM) (30%) Examp e 14 H NCOCH(CH )OP(O)(R)(O-M) (38%) One mole of anhydrous glycerol and one mole of phen- NC CH2CH2OP(O) (R) (OM) (64% ylphosphonic oxide are heated at 165 degrees centigrade until the mass liquefies, and then for 20 hours at 120 R represents the p-iluorophenyl radical (F C H degrees centigrade. The reaction mass treated in the man- M represents an equivalent of an alkali earth metal, ner described in Example 1, yields crude barium glyceryl and the Yleld 1S llldlcated in parenthesesphenylphosphonate. The crude salt is reduced to a very P-FIHOIOPhCIIYIPhOSPhOIIiC OXide ts With all the fine powder which is heated for a few minutes w1th ab- Other 810011015 mentioned 111 EXaIIIPIeS 1 to 15 to yield solute alcohol After cooling, one volume of acetone is the COITCSPOHdIIXg P- P Y P P monoesters added and the precipitate filtered off washed with alcohol T e pp y p p q e O e is prepared as and Vacuum dried. These operations are repeated on this fOHOWS according to the equatlonl 01 HO 3 0 p product until pure barium glyceryl phenylphosphonate is 38 grams (0.216 mole) of p-fluorophenylphosphonic obtained. The yield is 49' percent. acid and-64 grams (0.3 mole) of p-fluorophenylphos- HOCHPCHOH CH2OP(O)(CGHSMOBaM): phonyl d1chlor1de are heated at 200 degrees centigrade barium wglyceryl phenylphosphonate HOCH CH[OP(O)(C H )(OBa )]CH OHI the reaction). The excess of dichloride is distilled under barium fi-glyceryl phenylphosphonate reduced pressure. After cooling, the residue is heated with The determination of the neighboring groups 400 milliliters of dry benzene until complete dissolution. by the method of Malaprade indicates that the product 65 This solution is left for tWo days at 5 degrees centigrade te (p-fiuorophenylphosphonic oxide) 1s composed of 51.5 percent of barium a-glyceryl phenyl and the preclplta phosphonate and of 48.5 percent of the fiderivativa filtered off. The filtrate is left again for two days at 5 degrees centlgrade and a second amount of p-fluorophenyl- Example 15 phosphonic oxide is filtered off. The operation is repeated Calculated for (C H O FP) F, 12.0 percent; P, 19.6 percent; equivalent weight, 158.1. Found: F, 12.4 percent; P, 19.3 percent; equivalent weight, 160.

What is claimed is:

1. A compound represented by the formula wherein R is selected from the group consisting of halo- 10 12 2. A compound in accordance with claim 1 wherein R is alkyl of 1 to 8 carbon atoms.

3. A compound in accordance with claim 2 wherein R is p-fluorophenyl.

References Cited UNITED STATES PATENTS 2,360,302 10/1944 Etzler et al. 2 60-961 X 3,019,249 1/1962 Gundcrloy 260-961 X CHARLES B. PARKER, Primary Examiner. R. L. RAYMOND, Assistant Examiner.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,350,481 October 31, 1967 Emile Cherbuliez et a1.

It is certified that error appears in the above identified patent and that said Letters Patent are hereby corrected as shown below:

Column 1, line 18, "at" should read as Column 2, line 14, "particultarly" should read particularly Column 6, lines 17 to 21, the formula should appear as shown below:

0 OM ll OCH(CH F) 2 same column 6, line 22, "Yeld" should read Yield line 56, "propanedio-l,3" should read propanediol-l,3 r Column ll, line 11, "or" should read of Signed and sealed this 10th day of March 1970.

(SEAL) Attest:

EDWARD M.FLETCHER,JR. WILLIAM E. SCHUYLER, JR. Attesting Officer Commissioner of Patents 

1. A COMPOUND REPRESENTED BY THE FORMULA 